简介:食管鳞状细胞癌(ESCC)占所有食管肿瘤的90%以上。然而,ESCC发生和预后的分子机制尚不清楚,目前仍没有有效的分子生物标志物来诊断或预测ESCC患者的临床结局。这里,我们使用生物信息学分析来确定ESCC的潜在生物标志物和治疗靶点.方法:通过全面分析TCGA和GTEX的公开RNA-seq数据集,获得ESCC和正常食管组织样本之间的差异表达基因(DEGs)。基因本体论(GO)注释和Reactome途径分析确定了DEGs的生物学作用。此外,Cytoscape3.10.1平台和附属工具如CytoHubba用于可视化DEGs蛋白-蛋白相互作用(PPI)网络并识别hub基因,此外,我们的结果通过使用单细胞RNA分析进行了验证。结果:鉴定出2524个基因,这些基因在包括角质化在内的途径中表现出表达改变,表皮细胞分化,Gα信号事件,细胞增殖和分裂的生物学过程,细胞外基质(ECM)分解,和肌肉功能。此外,标志E2F目标的上调,G2M检查站,和TNF信号。CytoHubba揭示了20个hub基因,这些基因对这些患者的ESCC进展具有重要影响。其中,四个基因的高表达水平,CDK1MAD2L1、PLK1和TOP2A,与ESCC细胞系中细胞存活的关键依赖性相关,如CRISPR依赖评分所示,基因表达数据,和细胞系元数据。我们还确定了靶向这些基本枢纽基因的分子,其中GSK461364是有前途的PLK1抑制剂,BMS265246和Valrubicin抑制剂CDK1和TOP2A,分别。此外,我们发现,在ESCC患者中,MMP9的高表达与更差的总生存期相关。可能作为ESCC的潜在预后生物标志物或治疗靶标。单细胞RNA分析显示MMP9在骨髓中高表达,成纤维细胞,和上皮细胞,但T细胞含量低,内皮细胞,B细胞。这表明MMP9在肿瘤进展和基质重塑中的作用,强调其作为预后标志物和治疗靶点的潜力。讨论:我们的研究确定了ESCC中的关键枢纽基因,通过详细的表达和依赖性分析,评估其作为治疗靶点和生物标志物的潜力.值得注意的是,MMP9作为一个重要的预后标志物,高表达与低生存率相关。强调其靶向治疗的潜力。这些发现增强了我们对ESCC发病机制的理解,并突出了有希望的治疗途径。
Introduction: Esophageal squamous cell carcinoma (ESCC) accounts for over 90% of all esophageal tumors. However, the molecular mechanism underlying ESCC development and prognosis remains unclear, and there are still no effective molecular biomarkers for diagnosing or predicting the clinical outcome of patients with ESCC. Here, we used bioinformatics analysis to identify potential biomarkers and therapeutic targets for ESCC. Methodology: Differentially expressed genes (DEGs) between ESCC and normal esophageal tissue samples were obtained by comprehensively analyzing publicly available RNA-seq datasets from the TCGA and GTEX. Gene Ontology (GO) annotation and Reactome pathway analysis identified the biological roles of the DEGs. Moreover, the Cytoscape 3.10.1 platform and subsidiary tools such as CytoHubba were used to visualize the DEGs\' protein-protein interaction (PPI) network and identify hub genes, Furthermore our results are validated by using Single-cell RNA analysis. Results: Identification of 2524 genes exhibiting altered expression enriched in pathways including keratinization, epidermal cell differentiation, G alpha(s) signaling events, and biological process of cell proliferation and division, extracellular matrix (ECM) disassembly, and muscle function. Moreover, upregulation of hallmarks E2F targets, G2M checkpoints, and TNF signaling. CytoHubba revealed 20 hub genes that had a valuable influence on the progression of ESCC in these patients. Among these, the high expression levels of four genes, CDK1 MAD2L1, PLK1, and TOP2A, were associated with critical dependence for cell survival in ESCC cell lines, as indicated by CRISPR dependency scores, gene expression data, and cell line metadata. We also identify the molecules targeting these essential hub genes, among which GSK461364 is a promising inhibitor of PLK1, BMS265246, and Valrubicin inhibitors of CDK1 and TOP2A, respectively. Moreover, we identified that elevated expression of MMP9 is associated with worse overall survival in ESCC patients, which may serve as potential prognostic biomarker or therapeutic target for ESCC. The single-cell RNA analysis showed MMP9 is highly expressed in myeloid, fibroblast, and epithelial cells, but low in T cells, endothelial cells, and B cells. This suggests MMP9\'s role in tumor progression and matrix remodeling, highlighting its potential as a prognostic marker and therapeutic target. Discussion: Our study identified key hub genes in ESCC, assessing their potential as therapeutic targets and biomarkers through detailed expression and dependency analyses. Notably, MMP9 emerged as a significant prognostic marker with high expression correlating with poor survival, underscoring its potential for targeted therapy. These findings enhance our understanding of ESCC pathogenesis and highlight promising avenues for treatment.